[go: up one dir, main page]

EP1103543A1 - Nouveaux derives d'uree renfermant des heterocycles aromatiques azotes - Google Patents

Nouveaux derives d'uree renfermant des heterocycles aromatiques azotes Download PDF

Info

Publication number
EP1103543A1
EP1103543A1 EP99935077A EP99935077A EP1103543A1 EP 1103543 A1 EP1103543 A1 EP 1103543A1 EP 99935077 A EP99935077 A EP 99935077A EP 99935077 A EP99935077 A EP 99935077A EP 1103543 A1 EP1103543 A1 EP 1103543A1
Authority
EP
European Patent Office
Prior art keywords
ring
compound
hydrogen
lower alkyl
ethyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP99935077A
Other languages
German (de)
English (en)
Other versions
EP1103543A4 (fr
Inventor
Shiro Kenkyusho MITA
Masato Kenkyusho HORIUCHI
Masakazu Kenkyusho BAN
Hiroshi Kenkyusho SUHARA
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Santen Pharmaceutical Co Ltd
Original Assignee
Santen Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Santen Pharmaceutical Co Ltd filed Critical Santen Pharmaceutical Co Ltd
Publication of EP1103543A1 publication Critical patent/EP1103543A1/fr
Publication of EP1103543A4 publication Critical patent/EP1103543A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/335—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/14—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms

Definitions

  • the present invention relates to novel urea derivatives which have TNF- ⁇ production inhibitory effects and are useful as therapeutic agents for various diseases, particularly as therapeutic agents for autoimmune diseases such as rheumatoid arthritis.
  • TNF- ⁇ tumor necrosis factor- ⁇
  • TNF- ⁇ tumor necrosis factor- ⁇
  • TNF- ⁇ plays an important role in crises of rheumatoid arthritis and Crohn's disease, which are autoimmune diseases (Andreas Eigler et al., Immunology Today, 18 , 487, 1997).
  • TNF- ⁇ is known to participate in various diseases as well as autoimmune diseases such as rheumatoid arthritis, Crohn's disease and systemic lupus erythematosus as reported in the above-mentioned literatures and the like. Compounds which inhibit its production or suppress its effect are expected to be useful for treatment of various diseases, and many studies have been done. Outlines of these studies of drugs are introduced in the above-mentioned literatures (Yamazaki, Clinical Immunology, 27 , 1270, 1995, Andreas Eigler et al., Immunology Today, 18 , 487, 1997).
  • the present inventors focused attention on urea structure of which application to drugs had hardly been studied, made studies on synthesis of novel urea derivatives wherein sulfur is introduced into one side chain thereof and a nitrogen aromatic heterocycle is introduced into the other side chain thereof, and succeeded in preparing many novel compounds.
  • the present inventors further studied pharmacological actions of the compounds and found that these novel compounds have excellent TNF- ⁇ production inhibitory effects.
  • the present invention relates to compounds represented by the following general formula [I] or salts thereof (hereinafter referred to as "the present compound” as far as there is no proviso), and pharmaceutical compositions containing it as an active ingredient. [wherein
  • Each lower alkyl defined above can be substituted by cycloalkyl, cycloalkenyl, adamantyl, phenyl, halogen, hydroxy, lower alkoxy, or an aromatic or nonaromatic heterocycle having nitrogen in the ring.
  • Each phenyl defined above can be substituted by lower alkyl, phenyl, hydroxy, lower alkoxy, halogeno-lower alkoxy, halogen, nitro, carboxyl or ester thereof.
  • aromatic or nonaromatic heterocycle having nitrogen in the ring defined above can be substituted by lower alkyl, halogeno-lower alkyl, hydroxy-lower alkyl, cycloalkyl, phenyl, halogen, hydroxy or lower alkoxy.
  • the lower alkyl is straight-chain or branched alkyl having one to eight carbon atoms such as methyl, ethyl, propyl, butyl, hexyl, isopropyl, isobutyl, isopentyl, isohexyl, t-butyl or 3, 3-dimethylbutyl.
  • the lower alkenyl is straight-chain or branched alkenyl having two to eight carbon atoms such as vinyl, allyl, 3-butenyl, 5-hexenyl or isopropenyl.
  • the cycloalkyl is cycloalkyl having three to eight carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • the cycloalkenyl is cycloalkenyl having three to eight carbon atoms such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl.
  • the lower alkoxy is straight-chain or branched alkoxy having one to eight carbon atoms such as methoxy, ethoxy, propoxy, butoxy, hexyloxy, isopropoxy or t-butoxy.
  • the halogen is fluorine, chlorine, bromine or iodine.
  • the lower alkylene is straight-chain or branched alkylene having one to eight carbon atoms such as methylene, ethylene, propylene, tetramethylene, pentamethylene, hexamethylene, methylmethylene, ethylethylene, dimethylethylene, propylethylene, isopropylethylene or methylpropylene.
  • the aromatic heterocycle having nitrogen in the ring is a monocyclic or condensed polycyclic aromatic heterocycle having one or two nitrogen atoms in the ring such as pyridine, pyrimidine, pyrrole, imidazole, oxazole, thiazole, quinoline, indole, benzimidazole, benzoxazole or benzothiazole.
  • the nonaromatic heterocycle having nitrogen in the ring is a nonaromatic heterocycle having one or two nitrogen atoms in the ring such as pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine or homopiperazine.
  • the nonaromatic heterocycle having sulfur in the ring is a nonaromatic heterocycle having one or two sulfur atoms in the ring such as tetrahydrothiophene, thiolactone or dithiolane.
  • the ester is alkyl ester having one to eight carbon atoms such as methyl, ethyl or propyl, benzyl ester or phenyl ester.
  • thiol, hydroxy and nitrogen of the nonaromatic heterocycle or the aromatic heterocycle can be protected with a protecting group.
  • the protecting group of thiol is a usual protecting group of thiol such as acyl or substituted thio.
  • examples of the protecting group are acyl such as lower alkanoyl, phenylcarbonyl, thenoyl or nicotinoyl; ester such as lower alkoxycarbonyl or substituted lower alkoxycarbonyl; substituted thio such as lower alkylthio or phenylthio; and substituted carbamoyl.
  • acyl such as lower alkanoyl, phenylcarbonyl, thenoyl or nicotinoyl
  • ester such as lower alkoxycarbonyl or substituted lower alkoxycarbonyl
  • substituted thio such as lower alkylthio or phenylthio
  • carbamoyl substituted carbamoyl.
  • Each phenyl ring of the phenylcarbonyl and the phenylthio can be substituted by halogen, lower alkyl, lower alkoxy or nitro.
  • acyl such as acetyl, propionyl, butyryl, pivaloyl, benzoyl or thenoyl
  • ester such as t-butoxycarbonyl or benzyloxycarbonyl
  • substituted thio such as ethylthio, t-butylthio or phenylthio.
  • the protecting group of hydroxy is a usual protecting group of hydroxy such as acyl, substituted lower alkyl or substituted silyl.
  • examples of the protecting group are acyl such as formyl, lower alkanoyl, halogeno-lower alkanoyl or phenylcarbonyl; ester such as lower alkoxycarbonyl or phenyl-lower alkoxycarbonyl; substituted lower alkyl such as allyl, lower alkoxy-lower alkyl, substituted lower alkoxy-lower alkyl, phenyl-lower alkyl, tetrahydropyranyl or tetrahydrofuranyl; and substituted silyl such as lower alkylsilyl or phenylsilyl.
  • Each phenyl ring of the phenylcarbonyl, the phenyl-lower alkoxycarbonyl, the phenyl-lower alkyl and the phenylsilyl can be substituted by halogen, lower alkyl, lower alkoxy or nitro.
  • acyl such as formyl, acetyl, pivaloyl, monochloroacetyl, trichloroacetyl, trifluoroacetyl or benzoyl
  • ester such as methoxycarbonyl, ethoxycarbonyl, isobutoxycarbonyl, t-butoxycarbonyl or benzyloxycarbonyl: substituted alkyl such as allyl, methoxymethyl, 1-ethoxyethyl, 2-methoxyethoxymethyl, benzyloxymethyl, benzyl, 4-methoxybenzyl, trityl, 2-tetrahydropyranyl or 2-tetrahydrofuranyl; and substituted silyl such as trimethylsilyl, triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl or t-butyldiphenylsilyl.
  • the protecting group of nitrogen of the nonaromatic heterocycle or the aromatic heterocycle is a usual protecting group of amino such as acyl, substituted lower alkyl or substituted sulfonyl.
  • examples of the protecting group are acyl such as formyl, lower alkanoyl, halogeno-lower alkanoyl or phenylcarbonyl; ester such as lower alkoxycarbonyl, substituted lower alkoxycarbonyl or phenoxycarbonyl; substituted lower alkyl such as allyl, phenyl-lower alkyl or benzoyl-lower alkyl; and substituted sulfonyl such as lower alkylsulfonyl or phenylsulfonyl.
  • Each phenyl ring of the phenylcarbonyl, the phenoxycarbonyl, the phenyl-lower alkyl, the benzoyl-lower alkyl and the phenylsulfonyl can be substituted by halogen, lower alkyl, lower alkoxy or nitro.
  • acyl such as formyl, acetyl, trichloroacetyl, trifluoroacetyl or benzoyl
  • ester such as methoxycarbonyl, isobutoxycarbonyl, t-butoxycarbonyl, allyloxycarbonyl, 2, 2, 2-trichloroethoxycarbonyl, benzyloxycarbonyl, diphenylmethoxycarbonyl or phenoxycarbonyl
  • substituted alkyl such as allyl, benzyl, trityl or (4-methoxyphenyl)diphenylmethyl
  • substituted sulfonyl such as benzenesulfonyl, 2, 4, 6-trimethylbenzenesulfonyl or toluene-sulfonyl.
  • Salts in the present invention refer to any pharmaceutically acceptable salts, and examples thereof are salts with an inorganic acid such as hydrochloric acid, nitric acid or sulfuric acid, salts with an organic acid such as acetic acid, fumaric acid, maleic acid or tartaric acid, salts with an alkali metal or an alkaline-earth metal such as sodium, potassium or calcium, and the like.
  • an inorganic acid such as hydrochloric acid, nitric acid or sulfuric acid
  • salts with an organic acid such as acetic acid, fumaric acid, maleic acid or tartaric acid
  • salts with an alkali metal or an alkaline-earth metal such as sodium, potassium or calcium, and the like.
  • geometrical isomers or optical isomers are present in the present compounds, these isomers are also included in the scope of the present invention.
  • the present compounds can be in the form of hydrates.
  • Preferred examples of the present compound are compounds wherein the group(s) is (are) the followings in the compounds represented by the general formula [I] or salts thereof;
  • More preferred examples of the present compound are compounds wherein the group(s) is (are) the followings in the compounds represented by the general formula [I] or salts thereof;
  • the most preferred examples of the present compound are compounds wherein the group(s) is (are) the followings in the compounds represented by the general formula [I] or salts thereof;
  • the present compounds can be compounds wherein thiol, hydroxy, or nitrogen of the nonaromatic heterocycle or the aromatic heterocycle is protected with the protecting group or salts thereof in the above-mentioned preferred examples, more preferred examples, further preferred examples and most preferred examples of the compound or the salts thereof.
  • R 1 is the protecting group of the thiol.
  • compounds wherein thiol is protected with acetyl or salts thereof are preferable.
  • the present compound [I] can be synthesized through various synthesis routes, for example, as shown in the above reaction route scheme.
  • Each route is as follows. However, these routes exemplify typical routes and do not show all methods. Detailed synthesis methods are described in Examples later.
  • the compound [III] is reacted with the amino alcohol derivative [VI] in the presence of the condensation agent (for example, 1, 1'-carbonyldiimidazole [VII]) to convert it into the compound represented by the formula [IV]. Then, the compound [IV] is condensed with the thiol derivative [VIII] by Mitsunobu reaction to give the present compound [I].
  • the condensation agent for example, 1, 1'-carbonyldiimidazole [VII]
  • the compound [III] is reacted with the compound represented by the formula [IX] in the presence of the condensation agent (for example, 1, 1'-carbonyldiimidazole [VII]) to convert it into the compound represented by the formula [V]. Then, the compound [V] is deprotected with TBAF (tetra-n-butylammonium fluoride) to give the compound [IV]. Then, the present compound [I] is obtained in the same manner as by the route A).
  • the condensation agent for example, 1, 1'-carbonyldiimidazole [VII]
  • the compound [III] is reacted with the compound represented by the formula [X] in the presence of the condensation agent (for example, 1, 1'-carbonyldiimidazole [VII]) to give the present compound [I].
  • the condensation agent for example, 1, 1'-carbonyldiimidazole [VII]
  • the reactant when the reactant has a thiol, hydroxy or amino group in its molecule, these groups can be protected with suitable protecting groups, if necessary, and these protecting groups can also be removed by the conventional method after reaction.
  • the carboxyl group when the reactant has a carboxyl group in its molecule, the carboxyl group can be esterified, if necessary, and the ester can also be converted into a carboxylic acid by hydrolysis or the like.
  • the present compound when R 2 joins with sulfur adjacent to A 1 to form a thiolactone ring, the present compound can also be synthesized by the following methods other than the above-mentioned routes. Namely, when R 2 is carboxyl and R 1 is hydrogen in the formula [I], the thiolactone ring can also be synthesized by condensing these groups.
  • the compounds obtained by the above-mentioned methods can be converted into the above-mentioned salts by the conventional method.
  • the chemical structural feature of the present compounds is that the compounds have urea structure as basic structure and have a sulfur atom in one side chain and a nitrogen aromatic heterocycle in the other side chain respectively. Few studies of such drugs having the urea structure as basic skeleton have been reported. Moreover, no drug having a sulfur atom in a side chain has hitherto practically been reported. Limiting drugs to those having the TNF- ⁇ production inhibitory effects, which is an object of the present invention, no drug having a chemical structure similar to the present compound is known at all.
  • the present inventors precisely studied the synthesis of the compounds having the urea structure as basic structure which thus had been hitherto hardly studied, prepared the many novel compounds, found that these novel compounds have the excellent TNF- ⁇ production inhibitory effects, and completed the present invention.
  • the present compounds exhibit the effects both in state where the sulfur atom in the side chain joins with various groups (represented by R 1 in the formula [I] except for hydrogen) and in the state where the sulfur atom takes the form of SH (R 1 in the formula [I] is hydrogen).
  • R 1 plays a role as a protecting group of the SH group, the protecting group is sometimes removed by hydrolysis and the like and the resulting form of SH exhibits the effects.
  • the present compounds When the present compounds contain a carboxylate in their molecule, the present compounds exhibit the effects even in the ester state.
  • the ester linkage is sometimes subject to hydrolysis and the like and the resulting form of a carboxylic acid exhibits the effects.
  • the present compounds When the present compounds contain a group which is converted into a free hydroxy or amino group, the present compounds can be administered in state where these groups are protected with suitable protecting groups.
  • the present compounds can be administered in state where these protecting groups are removed.
  • TNF- ⁇ production inhibitory effects of the present compounds were examined in order to study utility of the present compounds. Details will be described in the item of pharmacological test below. Studying in vivo inhibitory effects on liberation of TNF- ⁇ caused by stimulation of lipopolysaccharide (LPS), the present compounds exhibited the excellent TNF- ⁇ production inhibitory effects.
  • LPS lipopolysaccharide
  • TNF- ⁇ production is known to be closely related to crises of autoimmune diseases such as rheumatoid arthritis, Crohn's disease and systemic lupus erythematosus, cachexia, acute infectious disease, allergy, pyrexia, anemia, diabetes and the like.
  • autoimmune diseases such as rheumatoid arthritis, Crohn's disease and systemic lupus erythematosus, cachexia, acute infectious disease, allergy, pyrexia, anemia, diabetes and the like.
  • Compounds which inhibit its production like the present compounds are expected to be useful for treatment of these various diseases.
  • the present compound can be administered orally or parnterally.
  • Examples of dasage forms are tablets, capsules, granules, powders, injections and the like.
  • the present compound can be formulated into preparations by the conventional methods.
  • oral preparations such as tablets, capsules, granules and powders can be produced by adding optionally diluents such as lactose, crystalline cellulose, starch and vegetable oil; lubricants such as magnesium stearate and talc; binders such as hydroxypropylcellulose and polyvinyl pyrrolidone; disintegrator such as calcium carboxymethylcellulose or low-substituted hydroxypropylmethylcellulose; coating agent such as hydroxypropylmethylcellulose, macrogol or silicone resin; or film forming agent such as gelatin film.
  • optionally diluents such as lactose, crystalline cellulose, starch and vegetable oil
  • lubricants such as magnesium stearate and talc
  • binders such
  • the dosage of the present compound can be selected suitably according to the symptom, age, dosage form and the like.
  • the present compound can be administered once to several times per day with a daily dose of 0.1 to 5000 mg, preferably 1 to 1000 mg.
  • N - [3-(4-Pyridyl)propyl]phthalimide (799 mg) and hydrazine monohydrate (600 mg) are dissolved in methanol (15 ml), and the solution is refluxed for four hours. After cooling, the reaction mixture is concentrated under reduced pressure, and chloroform is added to the residue. The organic layer is washed with a saturated aqueous sodium carbonate solution and saturated brine successively, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the titled compound (Reference compound No. 1-1, 366 mg).
  • Lithium aluminum hydride (370 mg) is suspended in anhydrous ether (14 ml) under a nitrogen atmosphere and ice cooling, and a solution of 4-(4-pyridyl)butyronitrile (705 mg) in anhydrous ether (10 ml) is added dropwise to the suspension. The mixture is stirred at room temperature for 2.5 hours. Anhydrous sodium sulfate is added to the reaction mixture under ice cooling, and water (0.5 ml) is added drop by drop thereto. Then, tetrahydrofuran is added thereto, and insoluble matter is filtered out. The filtrate is concentrated under reduced pressure to give the titled compound (Reference compound No. 3-1, 827 mg).
  • the resulting oily matter is purified by silica gel column chromatography and then dissolved in ethyl acetate (0.1 ml). A 4 N solution of hydrogen chloride in dioxane (0.65 ml) is added thereto under ice cooling. The resulting precipitate is filtered off to give the titled compound (Reference compound No. 6-1, 437 mg) as crystals.
  • Lithium aluminum hydride (358 mg) is suspended in anhydrous ether (22 ml) under a nitrogen atmosphere and ice cooling, and a solution of N-(2-hydroxyethyl)cyclooctylacetamide (998 mg) in anhydrous ether (8 ml) is added dropwise to the suspension. The mixture is stirred at room temperature overnight. Ethyl acetate and 0.1 N hydrochloric acid are added to the reaction mixture under ice cooling until foaming stops. Then, a 4 N aqueous sodium hydroxide solution is added to the whole to basify it, and the whole is extracted with ether.
  • Ammonium acetate (9.8 g) is added to a solution of 4-quinolinecarboxyaldehyde (2.0 g) in methanol (50 ml), and the mixture is stirred at room temperature for three hours. Further, sodium cyanoborohydride (1.0 g) is added to the mixture, and the whole is stirred for 40 minutes. The reaction mixture is poured into water, and the whole is concentrated under reduced pressure. The concentrate is extracted with chloroform. To the organic layer is added 1 N hydrochloric acid, and the whole is extracted. A 4 N aqueous sodium hydroxide solution is added to the hydrochloric acid extract to basify it, and then the whole is extracted with chloroform.
  • 1, 1'-Carbonyldiimidazole (3.60 g) is dissolved in a solution of 4-(aminomethyl)pyridine (2.00 g) in anhydrous tetrahydrofuran (62 ml) under a nitrogen atmosphere, and the mixture is stirred at room temperature for 10 minutes.
  • N-(2-Hydroxyethyl) - 2-cyclohexylethylamine hydrochloride (4.64 g) is added to the reaction mixture, and the whole is refluxed for two hours. Chloroform is added to the reaction mixture under ice cooling, and the whole is extracted.
  • Triethylamine (0.44 ml) and acetic anhydride (0.30 ml) are added to the reaction mixture under a nitrogen atmosphere, and the whole is stirred at room temperature for 20 minutes.
  • the reaction mixture is concentrated under reduced pressure, and 1 N hydrochloric acid is added to the residue to acidify it.
  • the aqueous layer is washed with ether.
  • a 1 N aqueous sodium hydroxide solution is added to the aqueous layer under ice cooling to basify it weakly, and the whole is extracted with ethyl acetate.
  • the organic layer is washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • the resulting oily matter is purified by silica gel column chromatography to give the titled compound (Compound No. 6-1, 0.50 g).
  • Methyl iodide (0.13 ml) is added to a solution of 1 - [2-(acetylthio)ethyl]-1-(2-cyclohexylethyl)-3-(4-pyridylmethyl)urea (Compound No. 4-1, 370 mg) in acetone (2 ml). The mixture is stirred overnight and then concentrated under reduced pressure, and the resulting precipitate is filtered off to give the titled compound (Compound No. 9-1, 386 mg) as crystals.
  • Formulation 1 in 100 mg Present compound 1 mg Lactose 66.4 mg Cornstarch 20 mg Calcium carboxymethylcellulose 6 mg Hydroxypropylcellulose 4 mg Magnesium stearate 0.6 mg
  • Tablets according to the formulation as above are coated with 2 mg/tablet of a coating agent (this is a conventional coating agent such as hydroxypropylmethylcellulose, macrogol or silicone resin) to obtain desired coated tablets. (The same is applied to tablets mentioned below.) Desired tablets can be obtained by changing the amounts of the present compound and the additives appropriately.
  • a coating agent this is a conventional coating agent such as hydroxypropylmethylcellulose, macrogol or silicone resin
  • Desired capsules can be obtained by changing the mixing ratio of the present compound to lactose appropriately.
  • Formulation 1 in 10 ml Present compound 10-100 mg Sodium chloride 90 mg Sodium hydroxide (or hydrochloric acid) q.s. Sterile purified water q.s.
  • Desired injections can be obtained by changing the mixing ratio of the present compound to the additives appropriately.
  • test compounds Female rats (five per group), body weight of about 200 g, about eight weeks old, were used as test animals. LPS from Salmonella was dissolved in physiological saline to prepare an LPS solution (1 mg/ml). Test compounds were dissolved or uniformly suspended in a 1% aqueous methylcellulose solution to give test compound preparation liquids.
  • the above-mentioned LPS solution (0.5 ml/kg) was subcutaneously administered to the rat.
  • the test compound preparation liquid (5 ml/kg, containing 10 mg/kg test compound) was orally administered.
  • blood was collected from abdominal aorta and was centrifuged at 4°C and 3000 rpm for ten minutes.
  • TNF- ⁇ levels in the obtained plasma were measured with a rat TNF- ⁇ -specific ELISA kit. TNF- ⁇ was not observed in the plasma with respect to an LPS-nonadministered group (control).
  • Table 1 shows TNF- ⁇ production inhibition rates (%) by oral administration of 10 mg/kg. Test compound Inhibition rate (%) Compound No. 4-2 72.5 Compound No. 4-3 80.8 Compound No. 4-15 77.3 Compound No. 4-16 77.2 Compound No. 4-17 70.6 Compound No. 4-18 64.2 Compound No. 5-1 74.9 Compound No. 5-2 81.2 Compound No. 8-1 80.0 Compound No. 8-3 78.9 Compound No. 8-4 81.0 Compound No. 8-10 69.0 Compound No. 8-11 63.6
  • the present compounds exhibit excellent TNF- ⁇ production inhibitory effects and have various medical uses as therapeutic agents for diseases in which TNF- ⁇ participates, for example, autoimmune diseases such as rheumatoid arthritis, Crohn's disease and systemic lupus erythematosus, cachexia, acute infectious disease, allergy, pyrexia, anemia, diabetes and the like.
  • the present invention provides novel urea derivatives which have TNF- ⁇ production inhibitory effects and are useful as therapeutic agents for various diseases, particularly as therapeutic agents for autoimmune diseases such as rheumatoid arthritis.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
EP99935077A 1998-08-05 1999-08-04 Nouveaux derives d'uree renfermant des heterocycles aromatiques azotes Withdrawn EP1103543A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
JP22150698 1998-08-05
JP22150698 1998-08-05
PCT/JP1999/004242 WO2000007985A1 (fr) 1998-08-05 1999-08-04 Nouveaux derives d'uree renfermant des heterocycles aromatiques azotes

Publications (2)

Publication Number Publication Date
EP1103543A1 true EP1103543A1 (fr) 2001-05-30
EP1103543A4 EP1103543A4 (fr) 2005-06-22

Family

ID=16767789

Family Applications (1)

Application Number Title Priority Date Filing Date
EP99935077A Withdrawn EP1103543A4 (fr) 1998-08-05 1999-08-04 Nouveaux derives d'uree renfermant des heterocycles aromatiques azotes

Country Status (6)

Country Link
US (1) US6420398B2 (fr)
EP (1) EP1103543A4 (fr)
KR (1) KR100663143B1 (fr)
CN (1) CN1147469C (fr)
CA (1) CA2339525A1 (fr)
WO (1) WO2000007985A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1561749A1 (fr) * 2000-05-31 2005-08-10 Santen Pharmaceutical Co., Ltd. Inhibiteurs de la production de TNF-Alpha pour le traitement de maladies auto-immunes
EP1457205A4 (fr) * 2001-11-30 2006-07-05 Santen Pharmaceutical Co Ltd Inhibiteur d'angiogenese
WO2009071448A1 (fr) * 2007-12-05 2009-06-11 Basf Se Composés pyridylméthyle sulfonamide
WO2010057101A3 (fr) * 2008-11-17 2010-07-15 Schering Corporation Composés utiles en tant qu’inhibiteurs de vih

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1172358A4 (fr) 1999-04-07 2003-04-02 Santen Pharmaceutical Co Ltd D riv s d'ur e n-substitu s-n'-substitu s et compositions pharmaceutiques contenant ces d riv s
WO2000061552A1 (fr) * 1999-04-07 2000-10-19 Santen Pharmaceutical Co., Ltd. DERIVE D'UREE N-SUBSTITUE-N'-SUBSTITUE, ET SON UTILISATION COMME INHIBITEUR DE LA PRODUCTION DE TNF-$g(a)
ATE349210T1 (de) 2002-07-09 2007-01-15 Boehringer Ingelheim Pharma Pharazeutische zusammensetzungen aus anticholinergica und p38 kinase hemmern zur behandlung von erkrankungen der atemwege
WO2005014532A1 (fr) * 2003-08-08 2005-02-17 Transtech Pharma, Inc. Composes aryle et heteroaryle, compositions et procedes associes
US20060035893A1 (en) 2004-08-07 2006-02-16 Boehringer Ingelheim International Gmbh Pharmaceutical compositions for treatment of respiratory and gastrointestinal disorders
PE20060777A1 (es) 2004-12-24 2006-10-06 Boehringer Ingelheim Int Derivados de indolinona para el tratamiento o la prevencion de enfermedades fibroticas
EP1992344A1 (fr) 2007-05-18 2008-11-19 Institut Curie P38 alpha comme cible therapeutique pour les maladies associées á une mutation de FGFR3
US7856879B2 (en) * 2007-12-11 2010-12-28 Memsic, Inc. Heater controller having improved start-up for thermal sensor
US8697740B2 (en) 2009-01-12 2014-04-15 Merck Sharp & Dohme Corp. Crystalline polymorphic forms of an antidiabetic compound

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS63246739A (ja) * 1987-04-01 1988-10-13 Fuji Photo Film Co Ltd ハロゲン化銀写真感光材料
FR2664269B1 (fr) * 1990-07-05 1992-10-02 Roussel Uclaf Nouveaux derives n-substitues d'alpha-mercapto alkylamines, leur procede de preparation, leur application a titre de medicaments et les compositions les renfermant.
GB9401129D0 (en) 1994-01-21 1994-03-16 British Bio Technology Hydroxamic acid derivatives as metalloproteinase inhibitors

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7345064B2 (en) 2000-05-31 2008-03-18 Santen Pharmaceutical Co., Ltd. TNF-α production inhibitors
US7923461B2 (en) * 2000-05-31 2011-04-12 Santen Pharmaceutical Co., Ltd. TNF-α production inhibitors
US7491739B2 (en) 2000-05-31 2009-02-17 Santen Pharmaceutical Co., Ltd. TNF-α production inhibitors
US7098226B2 (en) 2000-05-31 2006-08-29 Santen Pharmaceutical Co., Ltd. TNF-α production inhibitors
EP1743885A2 (fr) 2000-05-31 2007-01-17 Santen Pharmaceutical Co., Ltd. Inhibiteurs de la production de TNF-Alpha pour le traitement de maladies autoimmunes
EP1743885A3 (fr) * 2000-05-31 2007-03-14 Santen Pharmaceutical Co., Ltd. Composés de 1-[(adamantyl)alkyl]-3-[(pyridinyl)alkyl]urée comme inhibiteurs de la production de TNF-.alpha utiles pour le traitement de maladies autoimmunes
EP1568692A1 (fr) * 2000-05-31 2005-08-31 Santen Pharmaceutical Co., Ltd. (pyridin-4-yl)alkyl-amides comme inhibiteurs de la production de TNF-alpha
EP1561749A1 (fr) * 2000-05-31 2005-08-10 Santen Pharmaceutical Co., Ltd. Inhibiteurs de la production de TNF-Alpha pour le traitement de maladies auto-immunes
KR100944174B1 (ko) * 2001-11-30 2010-02-24 산텐 세이야꾸 가부시키가이샤 혈관 신생 저해제
US7741346B2 (en) 2001-11-30 2010-06-22 Santen Pharmaceutical Co., Ltd. Angiogenesis inhibitor
EP1457205A4 (fr) * 2001-11-30 2006-07-05 Santen Pharmaceutical Co Ltd Inhibiteur d'angiogenese
WO2009071448A1 (fr) * 2007-12-05 2009-06-11 Basf Se Composés pyridylméthyle sulfonamide
US8299262B2 (en) 2007-12-05 2012-10-30 Basf Se Pyridylmethyl-sulfonamide compounds
WO2010057101A3 (fr) * 2008-11-17 2010-07-15 Schering Corporation Composés utiles en tant qu’inhibiteurs de vih

Also Published As

Publication number Publication date
WO2000007985A1 (fr) 2000-02-17
CA2339525A1 (fr) 2000-02-17
CN1147469C (zh) 2004-04-28
KR20010072254A (ko) 2001-07-31
EP1103543A4 (fr) 2005-06-22
US20010041725A1 (en) 2001-11-15
CN1318051A (zh) 2001-10-17
KR100663143B1 (ko) 2007-01-02
US6420398B2 (en) 2002-07-16

Similar Documents

Publication Publication Date Title
JP4343690B2 (ja) プロテアーゼ阻害薬としてのシアノアルキルアミノ誘導体
EP1568692B1 (fr) (Pyridinyl)alkyl-amides ou -urées comme inhibiteurs de la production de TNF-alpha
US7462634B2 (en) N-(pyridin-2-yl)-sulfonamide derivatives
JP2002515900A (ja) 芳香族スルホニルアルファ−ヒドロキシヒドロキサム酸化合物
US20080312237A1 (en) Amide derivatives as ion-channel ligands and pharmaceutical compositions and methods of using the same
US6420398B2 (en) Urea derivatives having nitrogen aromatic heterocycle
HUT77608A (hu) Heterociklusos vegyületek felhasználása dopamin-D3-receptor ligandumként
JP2004523583A5 (fr)
AU2002352663A1 (en) Cyanoalkylamino derivatives as protease inhibitors
SK73898A3 (en) Metalloproteinase inhibitors, pharmaceutical compositions containing them and their pharmaceutical uses, and methods and intermediates useful for their preparation
JP2002513409A (ja) アミド芳香環スルホンアミドヒドロキサム酸化合物
WO2008053913A1 (fr) Dérivé de sulfonylurée capable d'inhiber sélectivement mmp-13
CZ20013155A3 (cs) Inhibitory metaloproteas
FR2569694A1 (fr) Derives d'ethylenediaminemonoamide, composition pharmaceutique les contenant et utilisation de ces composes a titre d'antidepresseur ou d'antiparkinsonien
SK12452001A3 (sk) Zlúčenina vytvárajúca inhibítor metaloproteinázy, farmaceutický prostriedok, spôsob prípravy liečiva a liečivo
JPS61218570A (ja) 新規複素環アミド化合物、およびそれらを含有する医薬組成物
US20220185785A1 (en) Inhibitors of cd40-cd154 binding
EP0598123A1 (fr) Derive de piperazine et medicament contenant ce derive
JP2003505367A (ja) マトリックスメタロプロテイナーゼ阻害剤としての３−アリールスルホニル−２−（置換メチル）プロパン酸誘導体
JPS6011702B2 (ja) 抗炎症作用化合物
SK5082002A3 (en) Beta disubstituted metalloprotease inhibitors
JP3472917B2 (ja) 含窒素芳香族複素環を有する新規ウレア誘導体
EP1098888A1 (fr) Derives de piperazinones et leurs applications
JP2002520393A (ja) 抗血栓剤としてのビスピペリジン
US20090137637A1 (en) Tetrazolyl-Methylene Amino Acid Derivatives

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20010305

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

A4 Supplementary search report drawn up and despatched

Effective date: 20050511

17Q First examination report despatched

Effective date: 20080709

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20100302